Flow of potassium into cells implicated in schizophrenia

May 6, 2009

This shows areas in the prefrontal cortex (right) and hippocampus (left) where activity differed in healthy control subjects during thinking tasks, depending on whether they had the risk version of the KCNH2 potassium channel gene. The image is made from functional magnetic resonance imaging data superimposed on 3-D MRI reconstruction of the brain. Credit: NIMH Genes Cognition and Psychosis Program

A study on schizophrenia has implicated machinery that maintains the flow of potassium in cells and revealed a potential molecular target for new treatments. Expression of a previously unknown form of a key such potassium channel was found to be 2.5 fold higher than normal in the brain memory hub of people with the chronic mental illness and linked to a hotspot of genetic variation.

An extensive series of experiments suggest that selectively inhibiting this suspect form could help correct disorganized brain activity in schizophrenia - without risk of cardiac side effects associated with some existing antipsychotic medications. Scientists at the National Institutes of Health and European colleagues report on threads of converging evidence in the May, 2009 issue of the journal Nature Medicine.

"The end game in linking genes with complex disorders like schizophrenia requires that we not only demonstrate statistical association, but also show how a gene version acts biologically to confer risk," explained Daniel Weinberger, M.D., director of National Institute of Mental Health's (NIMH) Genes Cognition and Psychosis Program, who led the research. "We found schizophrenia-like effects in brain circuitry and mental processing in perfectly healthy people who carry the risk-associated version of this potassium channel gene, even though they don't show any psychotic behavior."

Evidence suggests that schizophrenia stems from complex interactions between multiple genes and environmental factors. Several candidate genes have recently been statistically linked to the illness in large genome-wide association studies.

"Our study goes further, spanning discovery of a new gene variant, confirmation of its association with the illness, and multi-level probes into how it works - in human post mortem brain tissue, the living human brain, and neurons," added Weinberger.

By regulating the flow of potassium ions into the cell, potassium channels control when neurons fire - electrically discharge and release a chemical messenger that signals neighboring neurons in a circuit. This flow is regulated, in part, by activity of the chemical messenger dopamine, the main target of antipsychotic medications used to treat schizophrenia.

One type of potassium channel, called KCNH2, attracted the researchers' interest for its potential role in sustaining the type of neuronal firing that supports the higher mental functions disturbed in schizophrenia. Spurred by hints from postmortem studies of genetic variation linked to schizophrenia in the genomic neighborhood of KCNH2, the researchers analyzed the gene's association with the illness in 5 independent samples comprising hundreds of families. This pinpointed 4 variations associated with schizophrenia within a small region of the KCNH2 gene.

"Yet this statistical association didn't imply a mechanism," said Weinberger. "It didn't explain how KCNH2 might increase risk for schizophrenia. So we went back to the post-mortem brain tissue in search of an answer."

It was only then that the researchers discovered a previously unknown version of KCNH2, called Isoform 3.1, that soared to levels 2.5 times higher-than-normal in the hippocampus (memory hub) of people who had schizophrenia - especially those with the risk-associated variations. Isoform 3.1 was also higher-than-normal in healthy individuals who carried the risk-associated variations. This signaled the existence of a risk-associated version of the KCNH2 gene.

Healthy controls carrying the risk gene version also:

Performed significantly worse-than-normal on measures of IQ and mental processing speed. Previous studies have linked similar performance with genetic risk for schizophrenia.

Inefficiently processed memory in the hippocampus and working memory in the prefrontal cortex, as revealed by functional MRI (magnetic resonance imaging) scans. Although they performed similarly to controls on these tasks, their brains had to work harder to compensate for disordered tuning of circuitry - a phenomenon previously implicated in schizophrenia.

Showed levels 1,000 times lower in the heart than the other main form of KCNH2 and does not exist in lower animals, suggesting that it has evolved a unique role in the primate brain. Mutant forms of KCNH2 in the heart can lead to arrhythmias and even sudden death - a rare risk of taking antipsychotic medications, many of which interact with KCNH2. So targeting this brain-specific form potentially opens the way to development of new treatments free of such cardiac side-effects.

Dramatically changed activity in rodent brains toward a neuronal firing pattern that may be important for thinking and memory tasks unique to primates.

Is expressed much more prior to birth, compared to the other main form of KCNH2, suggesting that it plays a prominent role in the early stages of brain development.

Is associated with a hotspot of variation in an area that controls gene expression, hinting that the suspect variations may contribute to schizophrenia risk by over-expressing Isoform 3.1.

Even though it is normally important for our higher order executive functioning, such over expression of Isoform 3.1 in schizophrenia could result in "abnormally increased neuronal excitability, runaway circuit activity and inefficient information processing," suggested Stephen Huffaker, Ph.D., the article's lead author, now a medical student at Harvard. The researchers propose that a treatment designed to inhibit just Isoform 3.1, might spare any heart-related side effects while improving the disorganized neural firing characteristic of the brain in schizophrenia.

Related Stories

Recommended for you

Short telomeres—the protective caps on the ends of chromosomes—have been previously linked to increased risk of death from heart disease. Now, research by scientists at UC San Francisco and the Veterans Affairs Medical ...

Researchers led by ETH Professor Martin Fussenegger at the Department of Biosystems Science and Engineering (D-BSSE) in Basel have produced artificial beta cells using a straightforward engineering approach.

Loss of a key protein leads to defects in skeletal development including reduced bone density and a shortening of the fingers and toes—a condition known as brachydactyly. The discovery was made by researchers at Penn State ...

Medical students are taught that once infected with Toxoplasma gondii—the "cat parasite"—then you're protected from reinfection for the rest of your life. This dogma should be questioned, argue researchers in an Opinion ...

A team of scientists has uncovered details of the cellular mechanisms that control the direct programming of stem cells into motor neurons. The scientists analyzed changes that occur in the cells over the course of the reprogramming ...

Researchers from the University of Pittsburgh School of Medicine and UPMC have engineered a protein that reverses carbon monoxide (CO) poisoning in mice, a discovery that could potentially lead to the creation of the first ...

2 comments

As a sufferer of schizo-affective disorder, this is very exciting news. A potential new target for treatment. I can vouch for the fact that one's memory is poor after developing schizo symptoms. Also they provide a clue as to why I seem to have heart palpitations on an irregular basis.

This could have positive effects on the lack of continuing a medication regimen because of side effects and non-compliance. Knowing what problems can arise from personal family experience, this may be a gift to all concerned.

Please sign in to add a comment.
Registration is free, and takes less than a minute.
Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.